QSAR Modeling of a Set of Pyrazinoate Esters as Antituberculosis Prodrugs

Tuberculosis is an infection caused mainly by Mycobacterium tuberculosis. A first-line antimycobacterial drug is pyrazinamide (PZA), which acts partially as a prodrug activated by a pyrazinamidase releasing the active agent, pyrazinoic acid (POA). As pyrazinoic acid presents some difficulty to cross the mycobacterial cell wall, and also the pyrazinamide-resistant strains do not express the pyrazinamidase, a set of pyrazinoic acid esters have been evaluated as antimycobacterial agents. In this work, a QSAR approach was applied to a set of forty-three pyrazinoates against M. tuberculosis ATCC 27294, using genetic algorithm function and partial least squares regression (WOLF 5.5 program). The independent variables selected were the Balaban index (I), calculated n-octanol/water partition coefficient (ClogP), van-der-Waals surface area, dipole moment, and stretching-energy contribution. The final QSAR model (N = 32, r(2) = 0.68, q(2) = 0.59, LOF = 0.25, and LSE = 0.19) was fully validated employing leave-N-out cross-validation and y-scrambling techniques. The test set (N = 11) presented an external prediction power of 73%. In conclusion, the QSAR model generated can be used as a valuable tool to optimize the activity of future pyrazinoic acid esters in the designing of new antituberculosis agents.

Molecular modeling and QSAR studies of a set of indole and benzimidazole derivatives as H(4) receptor antagonists

Histamine is an important biogenic amine, which acts with a group of four G-protein coupled receptors (GPCRs), namely H(1) to H(4) (H(1)R - H(4)R) receptors. The actions of histamine at H(4)R are related to immunological and inflammatory processes, particularly in pathophysiology of asthma, and H(4)R ligands having antagonistic properties could be helpful as antiinflammatory agents. In this work, molecular modeling and QSAR studies of a set of 30 compounds, indole and benzimidazole derivatives, as H(4)R antagonists were performed. The QSAR models were built and optimized using a genetic algorithm function and partial least squares regression (WOLF 5.5 program). The best QSAR model constructed with training set (N = 25) presented the following statistical measures: r (2) = 0.76, q (2) = 0.62, LOF = 0.15, and LSE = 0.07, and was validated using the LNO and y-randomization techniques. Four of five compounds of test set were well predicted by the selected QSAR model, which presented an external prediction power of 80%. These findings can be quite useful to aid the designing of new anti-H(4) compounds with improved biological response.

Beauty, Class and Discourse: Issues in Debate

In this text we proceed through a brief review of Naomi Lee`s (2009) article, highlighting her significant contributions to social and cultural psychology. In our dialogue with her text we inquire about some arguments and methodological procedures she presents. We raise some specific questions related to how the issue of beauty is framed, and we ponder on how a broadening of the scope to include history-of ideas, of relations-would bring some important elements to her approach. As Lee relates beauty and class, we examine the nuanced meanings of lack and deficiency in her analytical work. We also discuss her assumptions and position concerning discourse and dialogue which mark her ways of proceeding through the analysis of the interviews. We speculate that the depersonalized answer appointed in the interviewees` discourse can be related to a way of considering beauty as disembodied.

Voltammetric determination of cocaine in confiscated samples using a cobalt hexacyanoferrate film-modified electrode

In this work, a fast, non destructive voltammetric method for cocaine detection in acetonitrile medium using a platinum disk electrode chemically modified with cobalt-hexacyanoferrate (CoHCFe) film is described. The deposition of CoHCFe film at platinum disk (working electrode) was carried out in aqueous solution containing NaClO(4) at 0.1 mol L(-1) as supporting electrolite. Stability studies of the film and subsequent voltammetric analysis of cocaine were made in acetonitrile medium with NaClO4 at 0.1 mol L(-1) as supporting electrolite. A reversible interaction between cocaine and CoHCFe at the film produces a proportional decrease of original peak current, due to the formation of a complex between cocaine and cobalt ions, with subsequent partial passivation of the film surface, being the intensity of current decrease used as analytical signal for cocaine. A linear dependence of cocaine detection was carried out in the range from 2.4 x 10 x 4 to 1.5 x 10(-3) mol L(-1), with a linear correlation coefficient of 0.994 and a detection limit of 1.4 x 10 x 4 mol L(-1). The analysis of confiscated samples by the proposed method indicated cocaine levels from 37% to 95% (m/m) and these results were validated by comparison to HPLC technique, being obtained good correlation between both methods. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

The time course of vasoconstriction and endothelin receptor A expression in pulmonary arterioles of mice continuously exposed to ambient urban levels of air pollution

The present study aimed to verify the time course of the effects of environmental levels of urban air pollution toxicity on lung arterioles. BALB/c mice (n = 56) were continuously exposed to selective chambers equipped with (filtered, F) or without (non-filtered, NF) filter devices for particles and toxic gases for 24 h/day, over 14, 21, 30 or 45 days. After exposure, we evaluated the lumen-wall relationship (an estimator of arteriolar narrowing), endothelial nitric oxide synthase (eNOS) and endothelin type A receptor (ETAr) expression in the vascular wall and inflammatory influx of the peribronchiolar area. Concentrations of fine particulate matter (PM <= 2.5 mu g/m(3)), nitrogen dioxide (NO(2)), black smoke (BS), humidity and temperature in both the environment and inside the chambers were measured daily. Filters cleared 100% of BS and 97% of PM inside the F chamber. The arteriole wall of the lungs of mice from NF chamber had an increased ETAr expression (p <= 0.042) concomitant to a decrease in the lumen/wall ratio (p = 0.02) on the early days of exposure, compared to controls. They also presented a progressive increment of inflammatory influx in the peribronchiolar area during the study (p = 0.04) and decrement of the eNOS expression on the 45th day of exposure in both vascular layers (p <= 0.03). We found that after 14 days of exposure, the ambient levels of air pollutants in Sao Paulo induced vasoconstriction that was associated with an increase in ETAr expression. These vascular results do not appear to be coupled to the progressive inflammatory influx in lung tissue, suggesting a down-regulation of vasoconstrictive mechanisms through an imbalance in the cytokines network. It is likely that these responses are protective measures that decrease tissue damage brought about by continuous exposure to air pollutants. (C) 2010 Elsevier Inc. All rights reserved.

Microcirculatory effects of local and remote ischemic preconditioning in supraceliac aortic clamping

Introduction: Supraceliac aortic clamping in major vascular procedures promotes splanchnic ischemia and reperfusion (I/R) injury that may induce endothelial dysfunction, widespread inflammation, multiorgan dysfunction, and death. We tested the hypothesis that local or remote ischemic preconditioning (IPC) may be protective against injury after supraceliac aortic clamping through the modulation of mesenteric leukocyte-endothelial interactions, as evaluated with intravital microscopy and expression of adhesion molecules. Methods: Fifty-six male Wistar rats (weight, 190 to 250 g), were divided into four groups of 14 rats each: control sham surgery without aortic occlusion; I/R through supraceliac aortic occlusion for 20 minutes, followed by 120 minutes of reperfusion; local IPC through supraceliac aortic occlusion for two cycles of 5 minutes of ischemia and 5 minutes of reperfusion, followed by the same protocol of the IR group; remote IPC through infrarenal aortic occlusion for two cycles of 10 minutes of ischemia and 10 minutes of reperfusion, followed by the same protocol of the IR group. Seven animals per group were used to evaluate in vivo leukocyte-endothelial interactions in postcapillary venules with intravital microscopy and another seven animals per group were used to collect mesentery samples for inmmnohistochemistry demonstration of adhesion molecules expression. Results: Supraceliac aortic occlusion increased the number of rolling leukocytes with slower velocities and increased the number of adherent leukocytes to the venular surface and leukocyte migration to the interstitium. The expression of P-selectin, E-selectin, and intercellular adhesion molecule-1 was also increased significantly after I/R. Local or remote IPC reduced the leukocyte recruitment in vivo and normalized the expression of adhesion molecules. Conclusions: Local or remote IPC reduces endothelial dysfunction on mesenteric microcirculation caused by I/R injury after supraceliac aortic clamping. (J Vase Surg 2010;52:1321-9.) Clinical Relevance: The present study demonstrates that ischemia and reperfusion injury induced by supraceliac aortic occlusion promotes endothelial dysfunction and leukocyte recruitment on mesenteric microcirculation. Local and remote preconditioning reduced leukocyte-endothelial interactions and normalized the expression of endothelial adhesion molecules involved in this process. Although we recognize the limitation of an experimental model, our findings suggest that local and remote ischemic preconditioning minimize the endothelial dysfunction and leukocyte recruitment events that play a central role in systemic inflammation and multiorgan dysfunction after major aortic reconstructions.

Furosemide impairs nasal mucociliary clearance in humans

Furosemide, a potent diuretic, affects ion and water movement across the respiratory epithelium. However, the effects of furosemide, as clinically used, on mucociliary clearance, a critical respiratory defense mechanism, are still lacking in humans. Fourteen young healthy subjects were assigned to three random interventions, spaced one-week apart: no intervention (control), oral furosemide (40 mg), and furosemide + oral volume replacement (F + R). Nasal mucociliary clearance was assessed by saccharine test (STT), and mucus properties were in vitro evaluated by means of contact angle and transportability by sneeze. Urine output and osmolality were also evaluated. Urine output increased and reduced urine osmolality in furosemide and F + R compared to the control condition. STT remained stable in the control group. In contrast, STT increased significantly (40%) after furosemide and F + R. There were no changes in vitro mucus properties in all groups. In conclusion, furosemide prolongs STT in healthy young subjects. This effect is not prevented by fluid replacement, suggesting a direct effect of furosemide on the respiratory epithelium. (C) 2010 Elsevier B.V. All rights reserved.

Experimental models of sepsis and their clinical relevance

Sepsis remains a major cause of morbidity and mortality mainly because of sepsis-induced multiple organ dysfunction. In contrast to preclinical studies, most clinical trials of promising new treatment strategies for sepsis have failed to demonstrate efficacy. Although many reasons could account for this discrepancy, the misinterpretation of preclinical data obtained from experimental studies and especially the use of animal models that do not adequately mimic human sepsis may have been contributing factors. In this review, the potentials and limitations of various animal models of sepsis are discussed to clarify to which extent these findings are relevant to human sepsis. Such models include intravascular infusion of endotoxin or live bacteria, bacterial peritonitis, cecal ligation and perforation, soft tissue infection, pneumonia or meningitis models using different animal species including rats, mice, rabbits, dogs, pigs, sheep, and nonhuman primates. Despite several limitations, animal models remain essential in the development of all new therapies for sepsis and septic shock because they provide fundamental information about the pharmacokinetics, toxicity, and mechanism of drug action that cannot be replaced by other methods. New therapeutic agents should be studied in infection models, even after the initiation of the septic process. Furthermore, debility conditions need to be reproduced to avoid the exclusive use of healthy animals, which often do not represent the human septic patient.

Effects of Tityus serrulatus scorpion venom on lung mechanics and inflammation in mice

The present study evaluated the effects of an intramuscular injection of Tityus serrulatus venom (TsV) (0.67 mu g/g) on lung mechanics and lung inflammation at 15, 30, 60 and 180 min after inoculation. TsV inoculation resulted in increased lung elastance when compared with the control group (p < 0.001): these values were significantly higher at 60 min than at 15 and 180 min (p < 0.05). Resistive pressure (Delta P(1)) values decreased significantly at 30, 60 and 180 min after TsV injection (p < 0.001). TsV inoculation resulted in increased lung inflammation, characterised by an increased density of mononuclear cells at 15, 30, 60 and 180 min after TsV injection when compared with the control group (p < 0.001). TsV inoculation also resulted in an increased pulmonary density of polymorphonuclear cells at 15, 30 and 60 min following injection when compared to the control group (p < 0.001). In conclusion, T serrulatus venom leads to acute lung injury, characterised by altered lung mechanics and increased pulmonary inflammation. (C) 2009 Elsevier Ltd. All rights reserved.

Pulmonary mechanic and lung histology injury induced by Crotalus durissus terrificus snake venom

In the present work we investigated the effects of Crotalus durissus terrificus venom (CdtV) on the pulmonary mechanic events [static and dynamic elastance, resistive (Delta P1) and viscoelastic pressures (Delta P2)] and histology after intramuscular injection of saline solution (control) or venom (0.6 mu g/g). The static and dynamic elastance values were increased significantly after 3 It of venom inoculation, but were reduced at control values in the other periods studied. The Delta P1 values that correspond to the resistive properties of lung tissue presented a significant increase after 6 h of CdtV injection, reducing to basal levels 12 h after the venom injection. In Delta P2 analysis, correspondent to viscoelastic components, an increase occurred 12 h after the venom injection, returning to control values at 24 h. CdtV also caused an increase of leukocytes recruitment (3-24 h) to the airways wall as well as to the lung parenchyma. In conclusion, C. durissus terrificus rattlesnake venom leads to lung injury which is reverted, after 24 h of inoculation. (c) 2008 Elsevier Ltd. All rights reserved.

Leukocytoclastic vasculitis: another condition that mimics syphilis

Syphilis, a disease that in the past was associated with significant morbidity and lethality rates, has resurged in recent years principally as a consequence of changes in risk behavior. An epidemiological group that is commonly affected is the HIV-infected population. The characteristics of the disease and its progression may differ in these patients. The present report describes a case of an HIV-positive male patient, who developed florid secondary syphilis: in addition to syphilitic roseola, he also presented with bilateral panuveitis and involvement of the central nervous system. Investigation revealed the prozone phenomenon and histological examination of the skin lesions showed the presence of leukocytoclastic vasculitis. This finding is extremely rare and few cases have been documented.

Adenosine deaminase and tuberculous meningitis-A systematic review with meta-analysis

Tuberculous meningitis (TBM) is a severe infection of the central nervous system, particularly in developing countries. Prompt diagnosis and treatment are necessary to decrease the high rates of disability and death associated with TBM. The diagnosis is often time and labour intensive; thus, a simple, accurate and rapid diagnostic test is needed. The adenosine deaminase (ADA) activity test is a rapid test that has been used for the diagnosis of the pleural, peritoneal and pericardial forms of tuberculosis. However, the usefulness of ADA in TBM is uncertain. The aim of this study was to evaluate ADA as a diagnostic test for TBM in a systematic review. A systematic search was performed of the medical literature (MEDLINE, LILACS, Web of Science and EMBASE). The ADA values from TBM cases and controls (diagnosed with other types of meningitis) were necessary to calculate the sensitivity and specificity. Out of a total of 522 studies, 13 were included in the meta-analysis (380 patients with TBM). The sensitivity, specificity and diagnostic odds ratios (DOR) were calculated based on arbitrary ADA cut-off values from 1 to 10 U/l. ADA values from 1 to 4 U/l (sensitivity > 93% and specificity < 80%) helped to exclude TBM; values between 4 and 8 U/l were insufficient to confirm or exclude the diagnosis of TBM (p = 0.07), and values > 8 U/l (sensitivity < 59% and specificity > 96%) improved the diagnosis of TBM (p < 0.001). None of the cut-off values could be used to discriminate between TBM and bacterial meningitis. In conclusion, ADA cannot distinguish between bacterial meningitis and TBM, but using ranges of ADA values could be important to improve TBM diagnosis, particularly after bacterial meningitis has been ruled out. The different methods used to measure ADA and the heterogeneity of data do not allow standardization of this test as a routine.

Conservation of hepatitis C virus nonstructural protein 3 amino acid sequence in viral isolates during liver transplantation

As a consequence of selective pressure exerted by the immune response during hepatitis C virus (HCV) infection, a high rate of nucleotide mutations in the viral genome is observed which leads to the emergence of viral escape mutants. The aim of this study was to evaluate the evolution of the amino acid (aa) sequence of the HCV nonstructural protein 3 (NS3) in viral isolates after liver transplantation. Six patients with HCV-induced liver disease undergoing liver transplantation (LT) were followed up for sequence analysis. Hepatitis C recurrence was observed in all patients after LT. The rate of synonymous (dS) nucleotide substitutions was much higher than that of nonsynonymous (dN) ones in the NS3 encoding region. The high values of the dS/dN ratios suggest no sustained adaptive evolution selection pressure and, therefore, absence of specific NS3 viral populations. Clinical genotype assignments were supported by phylogenetic analysis. Serial samples from each patient showed lower mean nucleotide genetic distance when compared with samples of the same HCV genotype and subtype. The NS3 samples studied had an N-terminal aa sequence with several differences as compared with reference ones, mainly in genotype 1b-infected patients. After LT, as compared with the sequences before, a few reverted aa substitutions and several established aa substitutions were observed at the N-terminal of NS3. Sites described to be involved in important functions of NS3, notably those of the catalytic triad and zinc binding, remained unaltered in terms of aa sequence. Rare or frequent aa substitutions occurred indiscriminately in different positions. Several cytotoxic T lymphocyte epitopes described for HCV were present in our 1b samples. Nevertheless, the deduced secondary structure of the NS3 protease showed a few alterations in samples from genotype 3a patients, but none were seen in 1b cases. Our data, obtained from patients under important selective pressure during LT, show that the NS3 protease remains well conserved, mainly in HCV 3a patients. It reinforces its potential use as an antigenic candidate for further studies aiming at the development of a protective immune response.

Effects of biomass burning on nasal mucociliary clearance and mucus properties after sugarcane harvesting

Objective: Biofuel from sugarcane is widely produced in developing countries and is a clean and renewable alternative source of energy. However, sugarcane harvesting is mostly performed after biomass burning. The aim of this study was to evaluate the effects of harvesting after biomass burning on nasal mucociliary clearance and the nasal mucus properties of farm workers. Methods: Twenty seven sugarcane workers (21-45 years old) were evaluated at the end of two successive time-periods: first at the end of a 6-month harvesting period (harvesting), and then at the end of a 3-month period without harvesting (non-harvesting). Nasal mucociliary clearance was evaluated by the saccharine transit test, and mucus properties were analyzed using in vitro mucus contact angle and mucus transportability by sneeze. Arterial blood pressure, heart rate, respiratory rate, pulse oximetry, body temperature, associated illness, and exhaled carbon monoxide were registered. Results: Data are presented as mean values (95% confidence interval). The multivariate model analysis adjusted for age, body-mass index, smoking status and years of working with this agricultural practice showed that harvesting yielded prolonged saccharine transit test in 7.83 min (1.88-13.78), increased mucus contact angle in 8.68 degrees (3.18-14.17) and decreased transportability by sneeze in 32.12 mm (-44.83 to -19.42) compared with the non-harvesting period. No significant differences were detected in any of the clinical parameter at either time-period. Conclusion: Sugarcane harvesting after biomass burning negatively affects the first barrier of the respiratory system in farm workers by impairing nasal mucociliary clearance and inducing abnormal mucus properties. (C) 2011 Elsevier Inc. All rights reserved.

Ultrastructural aspects of lingual papillae in squirrel monkey (Saimiri sciureus)

Saimiri sciureus is one of the smallest Cebidae native of Amazon region and also found at the biological reserve of northeast Atlantic forest. It is an omnivore animal, with diversified diet that directly influences the lingual mucosa, which includes certain types of papillae with different organization levels. The present study attempted to describe the morphological and ultrastructure aspects of the dorsal surface of the S. sciureus. Five tongues of de S. sciureus were analyzed from three males and two females who died from natural causes and were obtained from breeding colonies of CENP-Ananindeua-PA. Main macroscopic features were a general triangular shape with a craniocaudal elongation pointed apex. Tissue samples-apex, body, and root of tongue-were fixed in modified Karnovsky solution, following standard scanning protocol, mounted in stubs, coated by gold, and analyzed by Scanning Electron Macroscopy (SEM). Four types of papillae were described: filiform (along all tissue extension with 154 mu m of diameter), fungiform (along all tissue extension with 272 mu m of diameter), vallate [just three units in caudal (dorsal) portion with 830 mu m of diameter] and foliate (one pair at caudolateral surface with similar to 13 projections and 3000 mu m in length). Data analysis indicates that the distribution and ultra structural morphology of the S. sciureus lingual papillae are some similar to other primates. Microsc. Res. Tech. 74:484-487, 2011. (C) 2010 Wiley-Liss, Inc.